Rat/MgrA, a Regulator of Autolysis, Is a Regulator of Virulence Genes in Staphylococcus aureus

Abstract

We have previously identified mgrA (rat) as a regulator of autolysis in Staphylococcus aureus. Besides its effect on autolytic activity, we recently found alterations in the expression of regulator and target virulence genes in the mgrA mutant. Northern analysis and transcription fusion assays showed that inactivation of mgrA has led to the downregulation of RNAIII of agr and hla and upregulation of sarS and spa. Although both SarA and agr are activators of ␣-hemolysin and a repressors of protein A synthesis, we found that the transcription of sarA was not affected in the mgrA mutant and vice versa, indicating that MgrA likely regulates hla and spa in a SarA-independent manner. Previously we have shown that SarT, a SarA homolog, is a repressor of hla and an activator of spa, presumably by activating SarS, however, analysis of the double sarT mgrA mutant for hla and spa transcription indicated that the mgrA-mediated effect is not mediated via sarT. Our results further demonstrated that the mgrA gene product regulates hla and spa expression in a dual fashion, with the first being agr dependent and the second agr independent. In the agr-independent pathway, MgrA binds directly to hla and the sarS promoter to modulate ␣-hemolysin and protein A expression. Thus, our studies here have defined the nature of interaction of mgrA with other regulators such as agr, sarS, and sarT and its role in regulating hla and spa transcription within the virulence regulatory network of S. aureus.Staphylococcus aureus, a member of the family Micrococcaceae, is a gram-positive bacterium that normally colonizes the epithelial surface in 30 to 40% of humans. Despite advances in antimicrobial therapy, S. aureus remains a major cause of infections in the hospital setting. The spectrum of diseases caused by this organism is extremely wide, ranging from superficial skin infections to deep abscesses (29). Many of these infections begin locally (skin and catheters) and subsequently spread to the bloodstream, putting patients at risk of developing endocarditis and other metastatic complications (45). The capacity to cause a myriad of infections is probably attributable to the organism's capacity to colonize and survive in diverse host niches during the infection process.

Reduced Vancomycin Susceptibility inStaphylococcus aureus, Including Vancomycin-Intermediate and Heterogeneous Vancomycin-Intermediate Strains: Resistance Mechanisms, Laboratory Detection, and Clinical Implications

“…Perhaps the most consistent transcriptional change observed for VISA strains is the downregulation of the spa gene (74,122,169,199,201,251,303). A possibly incomplete list of genes where the gene product has been shown to affect the transcription of spa includes agr (76,343), sarA (51,76,343), sarS (50), arlSR (85,86), sarT (304), srrAB (262), tcaR (200), mgrA (138), rot (240), ccpA (307), and sarZ (342). Potentially, a mutation in any of these regulatory genes could simultaneously increase vancomycin resistance and decrease protein A production.…”

The SarA protein family of Staphylococcus aureus

“…3). Two of the smaller SarA homologs, MgrA and SarZ, have more sequence similarity to the MarR protein of Gram-negative bacteria than to other smaller SarA proteins (Ingavale et al, 2005). Thus, the SarA protein family can be classified into three subfamilies: 1) single domain proteins (SarA, -R, -T, -V and -X and Rot); 2) double domain proteins (SarS, -U and -Y); and 3) MarR homologs (MgrA and SarZ) (Table 1).…”

“…Mutation of mgrA resulted in increased autolysis and decreased in agr, sarS and sarX transcription (Ingavale et al, 2005). Transcriptional profiling studies disclosed that MgrA regulates 355 genes, with upregulation in 175 and down-regulation in 180 (Luong et al, 2006).…”

“…Transcriptional profiling studies disclosed that MgrA regulates 355 genes, with upregulation in 175 and down-regulation in 180 (Luong et al, 2006). In particular, exoproteins are up-regulated and surface proteins are down-regulated by MgrA, consistent with an agr positive phenotype (Ingavale et al, 2005). The effect of MgrA on autolysis may be mediated by sarV which is a positive regulator of several autolytic enzymes (see below).…”

Various checkpoints prevent the synthesis ofStaphylococcus aureuspeptidoglycan hydrolase LytM in the stationary growth phase

“…Within S. aureus, expression of the autolysins is repressed by the action of the 2-component systems ArlSR 21 and LytSR, 22 and the transcriptional regulator MgrA. 23,24 The cidAB and lrgAB operons add another level of regulation since they control the transport of peptidoglycan hydrolases to the membrane (reviewed in peptidoglycan biosynthesis and turnover but its activity also leads to the stimulation of the 2 component system SaeRS. 25 The SaeRS system enhances expression of virulence factors that are involved in biofilm, host-pathogen interaction, and innate immune evasion.…”